Reacting systems and substrate diluting system of the type described above are in particular intended for use with chemical reactions that are to be carried out with high dilution of the substrate, with concomitant avoidance of low product yield and use of large amounts of solvent.
Industry is often faced with the problem that certain reactions must be carried out at low concentration and/or high dilution of one or more of the substrates. In one example of a category of reactions high substrate dilution should minimize the risk for the formation of unwanted impurities. This is for instance the case in cyclisation reactions, in particular intramolecular macrocyclisation reactions, used in the production of active pharmaceutical ingredients. Indeed, too high substrate concentrations in this type of reactions favour intermolecular reactions and lead to polymerisation of the substrate in the reaction medium or to the occurrence of other unwanted side-reactions, thereby seriously decreasing the yield to the desired product and the product purity. To keep the selectivity up towards the desired end product and also the purity of the end product high, the reaction is usually carried out with high dilution of the substrate. High substrate dilution however involves the use of large amounts of solvent. Where batch reactions are employed, frequently used solvent dilution rates for this type of reactions mount to 100-1000 l/mole of substrate to permit keeping substrate concentration sufficiently low. In other words, for the production of small quantities of an end product, often the use of large volumes of solvent and the use of large reactor volumes is required. This entails serious constraints to the industry. Similar unwanted intermolecular side-reactions have been observed in certain types of polymerization reactions e.g. in the synthesis of cyclic polymers. These reactions clearly also benefit from high dilution. Enzymatic reactions with substrate inhibition exemplify another type of reactions that are preferably carried out at high dilution of the substrate, as a too high substrate concentration often leads to declining catalytic activity of the enzyme. In other types of reactions, low concentration of the substrate or other reactants is necessary to avoid unwanted precipitation, which typically occurs at higher concentrations.
Clearly, the processes performing such reactions as known in the art require a high dilution of the substrate and/or of one or more of the reactants in a reaction medium, and hence inherently necessitate the use of large volumes of solvent and therewith the use of large volume reactors, to produce small quantities of an end product only, with small reaction product yields per unit volume of reactor.
US 2004/0220416 A1 discloses a so-called “fed-batch” process for the singlet oxygen oxidation of organic substrates during which water is selectively removed from the reaction mixture by means of a membrane. The organic substrate, which must be either soluble in water or in an organic solvent miscible with water, is initially introduced into a reactor together with the solvent and the catalyst. Into the reactor is then introduced 2-90% strength H2O2, slowly or in portions. Water is introduced together with the H2O2, and is also formed during the catalysed disproportionation of H2O2. Via a pump, the reaction mixture is passed into a membrane unit, where the catalyst, the unreacted substrate and the product already formed are retained in the retentate and immediately reintroduced into the reactor. Water is separated off as permeate through the membrane. Optionally present water-miscible organic solvent may simultaneously also be separated from the reaction mixture, whereupon distillative separation of the water from the organic solvent takes place, the water is discarded and the organic solvent is reintroduced into the reactor. The process of US 2004/0220416 A1 is a so-called “fed-batch” process, from which water, formed in the reaction and also coming in together with the H2O2 reactant, needs to be removed in order to avoid that the reaction mixture becomes increasingly diluted by the water. As a result, losses in yield and in the efficiency of the singlet oxygen 1O2 are prevented, as well as negative influences on the solubility, such as demixing. The purpose of the process of US 2004/0220416 A1 is to avoid dilution of the substrate, which is the opposite of the problem which is addressed by the present invention.
As a solution to the problem outlined above, related to improving the efficiency in performing chemical reactions under high dilution, it has been proposed to apply pseudo high dilution reaction conditions (K. Ziegler in “Methoden der Organischen Chemie” (Houben-Weil) vol 4/2, E. Müller, Ed. Georg Thieme Verlag, Stuttgart, 1955). “Simulated high dilution conditions” involves that a highly diluted solution of the substrate concerned is added at a slow supply rate to the reactor, which contains a relatively high concentration of the other reactants. In some cases, this method permits reducing solvent dilution rates used to typically 10-100 l/mol of substrate. However, when compared to dilutions used in conventional reactions which typically vary from 0.5-5 l/mol, this method still involves the use of relatively large solvent volumes, and the limited reactor capacity associated therewith still necessitates using large reactor volumes for low productivity and small product yields. Moreover, the simulated high dilution method, tends to be efficient only for those reactions in which the kinetic product is formed, and does not work for reactions that are reversible to any significant degree.
There is thus a need for a device and a method which are particularly suitable for use with reactions which have to be carried out at low concentration of one or more of the substrates. In particular there is a need for a device and a method which permits to perform reactions which are to be carried out in high dilution in reactors with a reduced volume, using reduced quantities of solvent, while providing a sufficiently high reaction yield and good selectivity to the desired reaction product. The present invention provides an answer to these needs.